The selective conversion of one functional group in a multifunctional feed substrate has been an area of continuous high interest throughout the chemical, pharmaceutical and agrochemical industry. In particular, halogen atoms are often incorporated next to other functional groups in active ingredients or in precursors of those active ingredients.
The objective of high selectivity has often been rather elusive, because most processes are prone to side reactions leading to significant amounts of byproducts. These side reactions are consuming valuable amounts of feed substrate, and the byproducts are often rather useless. Some of the byproducts may also be difficult to separate from the desired product. In cases where the desired product is an intermediate for the production of a further derivative, some of the byproducts may also be disturbing for further synthesis steps because they may be reactive in such downstream process step and may lead to undesired additional consumption of valuable raw materials and even to undesirable and/or unacceptable end product contamination.
Multi-step synthesis protocols of complex multifunctional chemicals more and more comprise catalytic conversion steps as these often outperform their stoichiometric alternatives with respect to atom efficiency and reduced waste generation. Reductive conversion steps with hydrogen gas as the reducing agent typically use metal based catalysts in order to proceed at rates of commercial interests.
Metals, however, often interfere with carbon-halogen bonds in organic compounds. Pd in particular is for instance capable of inserting into a carbon-halogen bond. Such behaviour is desired in its use as catalyst in so-called coupling reactions. Such reactions are often used as key steps in multi-step synthesis paths for complex organic compounds, such as active ingredients in pharmaceutical or agrochemical industry. In a coupling reaction, a halogen containing first fragment is coupled with a second fragment by means of a catalyst, in which the second fragment is coupled to the first fragment at the position where the halogen was originally located. The second fragment may be coupled via a large variety of functional groups, and different versions of such coupling reactions have often received specific names, such as the Heck coupling, which is using an olefin, the Sonogashira coupling, which is using an alkyne, the Suzuki coupling, which is using a boronic acid and the Stille coupling, which uses an alkyl tin group. This list is far from exhaustive, because many more different functional groups may possibly be used for such coupling.
Insertion of a metal such as Pd into a carbon-halogen bond in the presence of hydrogen but in the absence of a suitable fragment to couple usually results in the displacement of the halogen atom by a hydrogen atom and hence the loss of the halogen (X) as part of the substrate. Such hydrogenolysis reaction is especially enhanced in the presence of a base which may capture the liberated acid HX. This reaction may be used advantageously in some applications, such as environmental treatment of halogenated organic pollutants.
For the production of the halogenated fragments to be used in subsequent coupling reactions, or in case halogen atoms are required in the structure of the final product, the insertion of the metal catalyst into the carbon-halogen bond is not desired, as it usually leads to side reactions and associated material losses. Not all halogens are evenly sensitive for this dehalogenation side reaction. The risk for dehalogenation is particularly high with chlorine, bromine and iodine, and much lower with fluorine-containing substrates.
A variety of methods have therefore been attempted in order to increase the selectivity of metal catalyzed reductive aminations and selective hydrogenations of one functional group in the presence of one or more halogen atoms elsewhere in the substrate molecule, in particular for chlorine, bromine and iodine. The methods which are currently available in the prior art may be subdivided into three classes.
A first method involves the addition of modifiers to the reaction mixture or working into alternative reaction media. U.S. Pat. No. 6,429,335 B1 for instance discloses a process for the reductive amination of ortho-chlorobenzaldehyde with ammonia under 140 bar of hydrogen using Raney nickel or Raney cobalt to produce the primary amines ortho-chlorobenzylamine. The process operates in the presence of an amount of disodium tetraborate decahydrate (borax), optionally together with a small amount of bis(hydroxyethyl) sulphide, and obtains a product selectivity of at most 95.87% wt. The main byproduct is 3.19% wt of ortho-chlorobenzyl alcohol, and only 0.1% wt of benzylamine was found.
Cheng et al., in “The effect of water on the hydrogenation of o-chloronitrobenzene in ethanol, n-heptane and compressed CO2”, Applied Catalysis A: General 455 (2013), pp. 8-15, Elsevier, discloses the effect of water or the use of compressed carbon dioxide as the reaction medium on the hydrogenation of o-chloronitrobenzene to o-chloro aniline over 5% Pd or Pt on a carbon support as the catalyst. The reaction is performed at 35° C. and under a hydrogen pressure of 40 bar. The Pd catalysts however suffer of poor stability under these conditions.
Dan-Qian Xu et al, “Hydrogenation of ionic liquids: An alternative methodology toward highly selective catalysis of halonitrobenzenes to corresponding haloanilines”, Journal of Molecular Catalysis A: Chemical, 235 (2005), pp. 137-142, Elsevier, addresses the same reaction. The process uses Raney nickel, 5% Pt/C and 5% Pd/C catalysts in different ionic liquids, with methanol as the reference solvent. Markedly lower dehalogenation was observed with the ionic liquid catalyst systems as compared to the methanol reference. The drawback of the use of special reaction media or the addition of modifiers is the extra complexity which needs to be built into the process.
A second method involves modifying the catalyst support in order to improve the selectivity. US 2007/0078282 A1 performs in its Example 4 the reductive amination of F-benzaldehyde with a monometallic catalyst of nickel on carbon (Kataleuna 6504 K). Kratky V. et al, “Effect of catalyst and substituents on the hydrogenation of chloronitrobenzenes”, Applied Catalysis, A: General, 235 (2002), pp. 225-231, Elsevier, discloses a process for the liquid phase hydrogenation of chloronitrobenzene isomers to the corresponding chloroanilines. The process uses either a palladium on charcoal catalyst (Pd/C) or a palladium on sulphonated poly(styrene-co-divinylbenzene) catalyst (Pd/D). Only the Pd/D catalyst was activated, i.e. reduced prior to its use in the reaction. The highest selectivity obtained towards the desired end-product was lower than 95%. Significant dechlorination was observed, primarily of the feed substrate over the Pd/C catalyst, and of the reaction product over the Pd/D catalyst.
A third method involves modifying the parent hydrogenation catalysts with additional metals, so-called promoters. Wang, Y. et al., “A green synthesis route of ortho-chloroaniline: solvent-free selective hydrogenation of ortho-chloronitrobenzene over Pt—Ru/Fe3O4/C catalyst”, Catalysis Communications 19 (2012) 110-114, Elsevier, discloses the use of Pt—Ru/Fe3O4/C catalyst for the selective hydrogenation of o-chloro nitrobenzene at temperatures between 75 and 85° C. and a pressure between 17 and 40 bar. High conversion is reported with virtually no dehalogenation. U.S. Pat. No. 3,666,813 reports the use of Bi, Pb and Ag modified Pt/C catalysts and a Pb modified Pd/C catalyst for the hydrogenation of chlorinated nitrobenzenes at temperatures between 75 and 100° C. and a pressure of 750 psig. While the parent Pd and Pt catalyst showed complete (100%) dehalogenation under these conditions, the modified catalysts showed a reduced dehalogenation down to levels below 5%. Mahata, N. et al., “Promotional effect of Cu on the structure and chloronitrobenzene hydrogenation performance of carbon nanotube and activated carbon supported Pt catalysts”, Applied catalysis A: General 464-465 (2013)28-34, Elsevier, shows that the presence of Cu as a promoter in a Pt catalyst with carbon nanotubes or activated carbon as the support results in the reduction of the level of dehalogenation and an increase of the catalyst stability in the hydrogenation of chloronitrobenzene at 120° C. and 15 bar. U.S. Pat. No. 5,512,529 discloses the use of a platinum catalyst on an active carbon support and modified by copper in the hydrogenation of halonitro compounds to aromatic haloamines.
Pt based catalysts are frequently contemplated in case of sensitive hydrogenation reactions. Examples of Pt-based multimetallic catalysts may be found in GB 2024643, U.S. Pat. No. 3,546,297, EP 2301660 A1, and also in the articles by Han et al.:“Effect of transition metal (Cr, Mn, Fe, Co, Ni and Cu) on the hydrogenation properties of chloronitrobenzene over Pt/NiO2 catalysts”, Journal of Molecular Catalysis A: Chemical, vol. 209, No, 1-2, 1 Feb. 2004, pages 83-87, or by Coq et al.:“Influence of alloying platinum for the hydrogenation of chloronitrobenzene over PtM/Al2O3 catalysts with M=Sn, Pb, Ge, Al, Zn”, Journal of Molecular Catalysis, vol. 71, 1 Jan. 1992, pages 317-333. U.S. Pat. No. 3,499,034 discloses Pd—Pt catalysts which have been promoted with iron, Fe. US 2001/0056035 A1 discloses a series of multimetallic catalysts which are all based on iridium, Ir, doped with one or more additional metals. In a comparative example, US 2001/0056035 A1 uses a bimetallic catalyst with platinum in combination with copper, Cu. However, these catalysts are very costly because of the scarcity of the platinum or of the other precious metals involved.
U.S. Pat. No. 5,689,021 discloses the use of a Raney Nickel catalyst, prepared from the nickel-rich crystalline precursor Ni2Al3, and doped with the addition element molybdenum to obtain Ni2-x/Al3/Mox, with x=0.4±0.05, in order to selectively hydrogenate various halonitroaromatics to form the corresponding haloaminoaromatics. The hydrodehalogenation side reaction was found to be virtually nonexistent.
Other chemical pathways to obtain particularly valuable polyfunctional products containing halogens have also been explored.
The stoichiometric alternative to the catalytic reductive amination of o-chloro benzaldehyde to obtain o-chloro benzyldimethylamine is exemplified by WO 2013/017611 A1, which describes a process to obtain o-chloro-benzyldimethyl amine from o-chlorobenzyl chloride and dimethylamine. The yield of the reaction was at most 95.4% of theory. The reaction was performed without involving any catalyst and a chloride salt was obtained as an undesired byproduct. Such processes based on stoichiometric chemistry in general suffer from poor atom efficiency and production of large amounts of waste.
There therefore remains a need for a highly selective conversion in chemical reactions selected from the reductive amination and the selective hydrogenation of only the first functional group, on a substrate containing at least one further functional group containing a halogen atom. The desire is to achieve industrially acceptable reaction rates while keeping the further functional group containing the halogen atom substantially untouched and present in the reaction product.
It is an objective of the process according to the present invention to carry out the selected chemical reaction with a low degree of dehalogenation. Fluorine is known to be significantly less sensitive to dehalogenation than the heavier and more bulky halogens chlorine, bromine and/or iodine: a fluorine atom initially present in the feed substrate molecule therefore has a higher likelihood to remain present in the reaction product as compared to the other halogens. There therefore remains a particular need for a highly selective catalyst which will allow a low degree of dehalogenation in a substrate containing at least one further functional group containing chlorine, bromine and/or iodine.
The present invention aims to obviate or at least mitigate the above described problem and/or to provide improvements generally.